1. fMRI Studies of Motivation a. Dopamine Transporter Methylation and Reward Anticipation. In collaboration with Dr. Falk Lohoffs Section on Clinical Genomics and Experimental Therapeutics (CGET), we analyzed Monetary Incentive Delay (MID) task data to investigate if there was an effect of SLC6A3 methylation on reward processing. We found that percent methylation of SLC6A3 significantly predicted reward anticipation-related activity in the caudate and nucleus accumbens in alcohol dependent patients but not in healthy control individuals. Higher methylation may result in lower DAT transcription and expression in the striatum, which may in turn compromise dopamine reuptake. Compromised dopamine reuptake may impair decision-making associated with excess drug seeking. b. Dynamic MID Task for Neuroimaging Omega-3 and Reward in Adults with ADHD (NORAA) trial Study. A dynamic version of the MID task is being utilized in a collaboration with Dr. Hibbeln of the Section on Nutritional Neuroscience. In this study the effect of Omega-3 in adults with ADHD is being investigated, through the response of reward system circuitry. CNIRC has assisted in the design and oversees analysis of the imaging component of this study. c. Reward Incentive Delay (RID) Task for Ghrelin Study. We are currently analyzing the data from a study conducted by Dr. Leggios Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN). This study used the RID task, a modification of the MID task that uses food and beverage images as cues, to investigate the role of ghrelin, a neuropeptide involved in regulating hunger and reward perception, in alcohol craving and use in a population of non-treatment seeking heavy drinkers. In this task the neural regions associated with motivation and response to reward were assessed as the participants attempted to earn points for real alcohol and food rewards. d. Reward Incentive Delay with Shock (RIDs) Task. We have continued conducting a novel translational study to explore the neural correlates of aversion resistant alcohol addiction using a paradigm, which adds an aversive component to the RID task. Light drinkers and non-treatment seeking heavy drinkers are being enrolled in an fMRI study, where they are able to earn points for real alcohol and food rewards at the risk of receiving a small electric shock. This study is ongoing. Preliminary behavioral results indicate a difference between light and heavy drinkers for high threat alcohol. Heavy drinkers are more willing to risk receiving an electric shock in order to win alcohol points, indicated by a greater number of button presses during high threat alcohol trials. Preliminary neuroimaging results indicate that heavy drinkers have increased amygdala activation when participants see an alcohol cue in the high threat condition compared to light drinkers. Heavy drinkers show increased BOLD activation in the striatum and insula during alcohol miss feedback compared to light drinkers. This increase in activation may represent a prediction error signal, which is higher in the heavy drinkers due to the increased salience of the alcohol reward to this group. e. Effort Task. We have also examined effort-based valuation in a treatment-seeking alcohol dependent population and a comparison group of healthy controls. Participants underwent an fMRI scan during which they played a task, which instructed participants to exert effort, in order to earn a monetary reward. There were three trial types, two where the level of effort was indicated to the subject (low and high), and one experimental condition where there was no indication of the required effort. Behaviorally, AD were less motivated during high effort trials and were less willing to exert higher levels of effort when the effort level was undisclosed. During low effort and unknown effort cue presentation, AD displayed an increased BOLD signal in clusters containing the dorsal and ventral striatum, regions implicated in effort and motivational processing (Grodin et al., 2016). 2. fMRI Studies of Decision-Making Ultimatum Task. We have conducted a study utilizing a modified version of the Ultimatum Game, a paradigm where participants are given an offer which divides $20.00 between the participant and the proposer. Participants were given the option to accept or reject each offer. Previous studies have demonstrated that the insula plays a key role in processing perceived unfair offers. Our fMRI results indicate higher activation in the healthy controls (HCs) in the insular cortex to unfair offers (less than $15:$5 split) that were later rejected. HCs insula activation may have acted as a mediator between emotional responses versus the risk of rejecting such offers. An additional analysis was performed to test the hypothesis that the activity of the insula is different depending on the context (social versus non-social) where the offer is made. Our results show that context influences the activity of the insula during the offer, which may represent a difference (HC vs. AD) in the executive network when evaluating cues in social vs. non-social environments. 3. fMRI Studies of Stress In a collaborative study with Dr. Lohoffs CGET we have implemented an fMRI fear extinction task and are currently analysing the imaging data. The primary goal of this study is to evaluate the role and interaction of (epi)genetic factors, early life stress (ELS) exposure, and alcohol use disorder (AUD) on neuronal mechanisms of fear conditioning and extinction. 4. Experimental fMRI Studies and Treatments a. GSK Study. We provided the imaging expertise for an experimental treatment study investigating verucerfont (CRF receptor antagonist) as a potential treatment for participants with alcohol use disorders. (Schwandt et al. 2016). Despite the negative findings for the primary outcome (subjective craving), the imaging not only showed significant effects of the verucerfont, but also opened a question around the motivational effect of the CRF receptor antagonist. Currently we are testing this hypothesis by conducting analysis of functional connectivity in the same dataset. b. BMS Trier Data Analysis. In 2015 we completed an experimental medication study of Pexacerfont. While we did not find BOLD signal differences in an anxious treatment seeking population, we did observe predictable activation in the amygdala during the presentation of fearful faces in the placebo group, validating our fMRI measures (Kwako et al. 2015). Currently we are analyzing the imaging data of an fMRI self-referential experiment based on the Trier test, a stress inducing procedure. Our preliminary analyses indicate increased activation in the anterior cingulate and inferior frontal gyri in alcohol dependent patients when listening to self-referential stress scripts compared to non-self stress scripts. These differences were reduced in individuals who were treated with pexacerfont. c. Reward Incentive Delay with Scream (RIDsc) Task. We have implemented and prototyped a modified version of the MID task in which some trials contain a loud scream paired with a human face with a fearful expression. This task is currently being used in a study of Nalmefene by Dr. Ramchandanis Section on Human Psychopharmocology (HP). d. Ghrelin receptor antagonist and oxytocin experiments. We have assisted in the design and implementation of a number of tasks to stimulate craving and emotional responses for Dr. Leggios CPN for two studies. The first study involves use of ghrelin receptor antagonist study as a treatment for alcohol use disorder (AUD). The second study will investigate the neural effects of oxytocin on dopaminergic pathways with respect to motivated behaviors such as drug and social reward. We will also be responsible for fMRI data analyses for these studies.